There is a significant overlap with the neurobiology of stress and abuse of drugs such as amphetamine and cocaine. 3,4-methylenedioxymethamphetamine (MDMA), is an amphetamine derivative whose abuse has dramatically increased worldwide since the 1980s. Although MDMA produces a selective neurotoxicity to serotonin (5HT) terminals, the long-term functional consequences of MDMA use are less understood. Moreover, the interactions between prior exposure to MDMA and chronic stress have not been examined. Our preliminary studies indicate that 5HT, at the level of the ventral tegmental area (VTA), dampens MDMA-induced dopamine (DA) release in n. accumbens (NAcc). Consequently, prior MDMA-induced 5HT depletions may disinhibit psychostimulant-induced NAcc DA release, disrupt the normal 5HTergic modulation of this system, and enhance the stress-associated DAergic and rewarding aspects of abused drugs. It also is known that chronic stress markedly affects the hippocampus (HIPP). Since 5HT inhibits hippocampal glutamate transmission, exposure to chronic stress after MDMA-induced damage to 5HT terminals could enhance the vulnerability of the HIPP to the excitotoxic effects of glutamate. The resultant excitotoxicity to the HIPP may underlie the reported memory deficits observed in human MDMA abusers. While neither MDMA-induced damage to 5HT terminals nor stress alone may be sufficient to produce marked consequences, they may' interact synergistically to cause dramatic neurochemical and functional changes associated with enhanced drug abuse and cognitive deficits. The overarching hypothesis is that MDMA-induced neurotoxicity to 5HT terminals disinhibits DA release in the NAcc and glutamate release in the HIPP, each of which synergizes with chronic stress to enhance drug reward and produce excitotoxicity to the HIPP, respectively. This hypothesis will be tested by 2 Specific aims: (1) examine hippocampal glutamate release as well as learning and memory in MDMA pre-treated rats subsequently exposed to a mild chronic unpredictable stress regimen and (2) assess the neurotoxic effects of MDMA on chronic stress-induced changes in DA release during cocaine and MDMA self-administration. These studies have significant implications for the possible synergistic interactions between prior MDMA exposure, chronic stress, and the vulnerability to subsequent drug self-administration.